Intravascular tissue disruption

ABSTRACT

Disrupting tissue and devices and systems for disrupting tissue. The disclosure describes ways to deliver moieties to a target tissue, where the target tissue in general is not at the point of introduction, in such a way that minimal damage is produced in the tissue at the point of introduction. In some embodiments this is accomplished by jetting fluid at high velocity into the target tissue. The disclosure further describes novel agents deliverable in such systems for use in remodeling tissues. Some of these agents comprise a liquid while others do not. Additionally, although not specifically described in detail much of the disclosure may additionally be used in the delivery of therapeutic drugs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/351,962, filed Jan. 17, 2012; which is a continuation of U.S.application Ser. No. 13/071,436, filed Mar. 24, 2011, now U.S. Pat. No.8,840,601; which claims the benefit of U.S. Provisional Application No.61/317,231, filed Mar. 24, 2010, and U.S. Provisional Application No.61/324,461, filed Apr. 15, 2010, the disclosures of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Various treatments to bodily tissue have been attempted. Devices thatcan deliver a fluid from a distal end port of a catheter have beendescribed. Devices have been described that have a valve at a distalport that allows fluid to flow through the valve in an openconfiguration and prevents fluid from flowing through the valve in aclosed configuration. Devices have also been described that can createmicrofluidic pulsed jets at the distal end of a catheter. Additionally,intravascular devices that include elements that pierce lumen walls canbe deployed within a lumen and deliver medication into a lumen wall.Some devices have a plurality of delivery ports through which fluids aredelivered simultaneously. These devices and methods of use have one ormore shortcomings for which the disclosure herein compensates.

SUMMARY OF THE INVENTION

One aspect of the disclosure is a method of controlling the delivery offluid from a medical delivery device, comprising: a medical devicecomprising a distal delivery region comprising a plurality of fluidcontrols; and selectively regulating the flow of a fluid through theplurality of fluid controls. In some embodiments selectively regulatingcomprises allowing the fluid to be delivered from a first fluid controlwhile minimizing the fluid that is delivered from a second fluidcontrol. In some embodiments selectively regulating comprises increasingthe flow of fluid from a first fluid control without increasing the flowof fluid through a second fluid control. In some embodiments selectivelyregulating comprises increasing the fluid flow from a first fluidcontrol a first amount and increasing the flow of fluid from a secondfluid control a second amount, wherein the first amount is differentthan the second amount. In some embodiments selectively regulatingcomprising moving a first fluid control from a closed configuration toan open configuration without moving a second fluid control from aclosed configuration to an open configuration. Moving the first controlto the open configuration can comprise moving a first valve element witha first aperture therein relative to a second valve element with asecond aperture therein until the apertures are in alignment. Moving thefirst fluid control to the open configuration can cause the fluid toflow from the first control at a high velocity, while the fluid flowsout of the second fluid control at a low velocity. In some embodimentsselectively regulating comprises flowing the fluid out of a first fluidcontrol at a high velocity and flowing the fluid out of a second fluidcontrol at a low velocity.

One aspect of the disclosure is a method of regulating the volume of afluid delivered from a medical device, comprising: a medical devicecomprising a distal delivery region comprising a fluid control incommunication with a fluid source, wherein the fluid control comprises afirst control element with a first aperture therein and a second controlelement with a second aperture therein; positioning the distal deliveryregion near a target location within a patient; and regulating thevolume of fluid released from the fluid control by moving the aperturesinto alignment to increase the flow of the fluid through the fluidcontrol. In some embodiments the regulating step occurs independently oftransience generated at a fluid pressure source. In some embodiments thefluid source is disposed external to the patient, further comprisingmaintaining a substantially constant pressure at the fluid source. Themethod can further comprise varying the fluid velocity at the fluidcontrol to regulate the volume of fluid released. In some embodimentsregulating the volume of fluid released further comprises moving theapertures out of alignment to decrease the flow of fluid out of thefluid control. In some embodiments the first control element comprises afirst tubular member and the second control element comprises a secondtubular member disposed within the first tubular member, and whereinmoving the apertures into alignment comprises moving the first tubularmember relative to the second tubular member to thereby move the firstaperture relative to the second aperture. Moving the first tubularmember relative to the second tubular member can comprise at least oneof axial movement and rotational movement.

One aspect of the disclosure is a method of periluminal tissue damage,comprising positioning a delivery device within a lumen without piercingthe lumen wall; delivering a fluid agent from the delivery devicethrough the lumen wall; and damaging tissue peripheral to the lumen wallwith the fluid agent. In some embodiments the lumen wall comprises anintimal layer, and wherein the damaging step comprises damaging nervecells peripheral to the intimal layer of the lumen wall. Damaging cancomprise damaging nerves cells while minimally damaging tissue in theintimal layer of the vessel wall. The lumen wall can comprise a mediallayer, and wherein damaging comprises damaging tissue within the mediallayer. Damaging tissue can comprise damaging cells in at least one of amedial layer of the lumen and nerve cells disposed within theadventitial layer. A damage cross section can increases as the radialdistance from the intimal layer increases.

In some embodiments the delivery device comprises a first fluid controland a second fluid control, wherein delivering comprises delivering thefluid agent from the first fluid control to create a first damageregion, and delivering the fluid agent from the second fluid controlcreates a second damage region, wherein portions of the first and secondregions overlap. In some embodiments damaging comprises damaging tissuewith the direct mechanical interaction of the fluid. In some embodimentsdamaging is caused by chemical interactions with the fluid, such as ahypotonic, a hypertonic fluid, a fluid that self-heats on interactionwith tissue, a fluid that has a pH significantly different from the pHof the tissue, a fluid that comprises material toxic to the tissue, afluid that comprises material toxic to a particular tissue, a fluid thatcomprises material which becomes toxic on interaction with the tissue,or a fluid that comprises material which is capable of absorbing energydelivered from a source external to the body.

In some embodiments delivering a fluid agent from the delivery devicethrough the lumen wall comprises delivering the fluid agent towardsneural tissue peripheral to an intimal layer of the lumen. In someembodiments damaging comprises damaging renal nerve tissue peripheral toa lumen of a renal artery. In some embodiments damaging renal nervetissue reduces hypertension.

One aspect of the disclosure is an apparatus for releasing fluid withina patient's body, comprising: an elongate member comprising a distalregion comprising a plurality of fluid controls, a lumen extendingthrough the distal region and in fluid communication with the pluralityof fluid controls, wherein the lumen is adapted to be in fluidcommunication with a fluid source, wherein each of the plurality offluid controls is adapted to be selectively addressable to regulate thevolume of a fluid that is released from the lumen and out the pluralityof fluid controls.

In some embodiments the fluid control has a closed configuration and anopen configuration, wherein in the closed configuration a substantiallysmaller volume of fluid, such as no fluid, is allowed to be released outof the fluid control than in the open configuration. In the openconfiguration the fluid control can be adapted to release the fluid athigh velocity. In some embodiments the distal region comprises aplurality of fluid controls in fluid communication with the lumen, eachfluid control has open and closed configurations, and wherein each fluidcontrol is adapted to regulate the volume of fluid that is released fromthe fluid control when the fluid is delivered at high velocity. Theplurality of fluid controls can be adapted to be individually opened. Insome embodiments the fluid control is adapted to be in fluidcommunication with a fluid source maintained at a substantially constantpressure. The fluid control can control the volume of fluid that isreleased from the fluid control while the fluid source is maintained atthe substantially constant pressure.

One aspect of the disclosure is an apparatus for controllably releasingfluid within a patient's body, comprising: a first tubular element witha first aperture therein; a second tubular element with a secondaperture therein, wherein the second tubular element is disposed withinthe first tubular element and movable relative to the first tubularelement, wherein the second tubular element has a lumen therethroughadapted to be in fluid communication with a fluid source, and whereinthe apertures have an aligned configuration that allows a fluid to passfrom the lumen through the first and second apertures. In someembodiments the apertures have an aligned configuration that allows afluid to pass through the apertures at a high velocity. In someembodiments the second aperture has a smaller maximum dimension than amaximum dimension of the first aperture. In some embodiments theapparatus further comprises a fluid source maintained at substantially aconstant pressure. The apertures can be adapted to release a fluidtherethrough at high velocity. The apertures can have an alignedconfiguration that allows fluid to pass therethrough when the fluidsource is maintained at a substantially constant first pressure during afirst delivery cycle and when the fluid source is maintained at asubstantially constant second pressure during a second delivery cycle,wherein the first and second pressure are different. In some embodimentsthe first tubular element has a deformed treatment configuration whereinat least a portion of the first tubular element is adapted to engage alumen wall in which it is positioned. The deformed treatmentconfiguration can be substantially spiral-shaped. The apparatus canfurther comprise an expandable element that is adapted to deform thefirst tubular element into contact with the lumen wall. The expandableelement can comprise a balloon. The expandable element can be moveablerelative to the first tubular element to cause the first tubular elementto be deformed into the treatment configuration. In some embodiments theapparatus further comprises a piercing element in fluid communicationwith the first aperture and extending from the first aperture, whereinthe piercing element is adapted to pierce tissue and allow for the fluidto flow from the aperture and out of the piercing element. In someembodiments the apertures have a non-aligned configuration that isadapted to allow fluid to flow therethrough at a low velocity.

One aspect of the disclosure is an apparatus for controllably releasingfluid within a patient's body, comprising: an elongate member comprisinga distal end, a proximal end, and a therapy portion in between the ends;the therapy portion comprises a plurality of expandable elongateelements, each with a delivery configuration and a treatmentconfiguration, wherein each of the plurality of expandable elongateelements comprises a fluid control, and in the delivery configurationthe control faces a first direction and in the treatment configurationthe control faces a second direction different than first direction. Insome embodiments the second direction is generally orthogonal to alongitudinal axis of the elongate member. In some embodiments the firstdirection is substantially parallel to a longitudinal axis of theelongate member. In some embodiments the expandable elongate elementsare tubular elements, and wherein the fluid controls are provided byremoving sections from the tubular elements. In some embodiments thefluid controls are proximal to distal ends of the elongate elements. Insome embodiments the expandable elongate elements are adapted topreferentially bend in the region of the fluid ports in the treatmentconfigurations. In some embodiments the expandable elongate elements areself-expanding. In some embodiments the expandable elongate elements areactuatable.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the features and advantages of the presentdisclosure will be obtained by reference to the following detaileddescription that sets forth illustrative embodiments, in which theprinciples of the disclosure are utilized, and the accompanying drawingsof which:

FIG. 1 illustrates an exemplary delivery system adapted to remodeltissue.

FIG. 2 illustrates an exemplary delivery system including a fluidsystem.

FIGS. 3, 4, 5 and 6 illustrate an exemplary embodiment of a deliverysystem incorporating a fluid system and a plurality of expandabletubular elements.

FIGS. 7, 8, 9 and 10 illustrate an exemplary method of remodeling renalnerves surrounding a renal artery.

FIG. 11 illustrates an exemplary reconfigurable distal delivery regionthat is an extension of an elongate delivery member.

FIG. 12 illustrates a distal delivery region including an elongatetubular element that has a spiral procedural configuration.

FIG. 13 illustrates a distal delivery region including first and secondtubular elements that have spiral procedural configurations.

FIG. 14 illustrates an exemplary portion of a distal delivery region,wherein a spiral element comprises two spring elements on either side ofa valve.

FIGS. 15 and 16 illustrate perspective and end views, respectively, ofan exemplary embodiment of the distal delivery region that includes atubular element, and includes a plurality of penetrating remodelingelements.

FIGS. 17 and 18 illustrate exemplary embodiments of distal deliveryregion including a plurality of expandable tubular elements.

FIGS. 19 and 20 illustrate exemplary distal delivery regionsincorporating expandable balloons.

FIGS. 21, 22, 23 and 24 illustrate distal delivery regions that includeincorporates one or more apertures on outer and inner tubular members.

FIGS. 25 and 26 illustrate a spiraled distal delivery region expanded ina renal artery.

FIGS. 27, 28, 29, 30, 31 and 32 illustrate exemplary needle valves thatcan be activated from a proximal end of the delivery system.

FIGS. 33, 34 and 35 illustrate an exemplary embodiment of a meteringvalve configuration.

FIGS. 36 and 37 illustrate a distal delivery region includingpenetrating remodeling agents deployed within a section of a renalartery.

FIG. 38 illustrates an exemplary distal delivery region incorporating aremodeling element that is a needle with a helical configuration.

FIG. 39 illustrate a representation of the fluidic performance of theexemplary valve shown in FIG. 42.

FIG. 40 is a figurative representation of the delivery system in termsof its resistive fluidic characteristics.

FIG. 41 illustrates a representation of the expected outflow rate as afunction d given the resistance characteristics represented in FIG. 40and a constant pressure supply.

FIG. 42 provides a figurative representation of a delivery systemincorporating a distal fluid control configured as a shuttle valve.

FIG. 43 illustrates the system of FIG. 39, wherein the shuttle valve isreplaced by a needle valve.

FIG. 44 illustrates an exemplary distal delivery region wherein a fluidor gas may be used to eject a component capable of external excitationor alternatively a component which upon ejection springs into a shapedifferent than its delivery shape and in so doing damages tissue in itsvicinity, thereby causing tissue remodeling.

FIG. 45 illustrates a distal delivery region comprising slicing hooks orsimple blades which cut tissue on being advanced.

FIG. 46 illustrates an exemplary distal delivery region comprising anatherectomy blade that can be spun to facilitate the requisite tissueremodeling.

FIG. 47 illustrates an exemplary distal delivery region similar to thatin FIG. 36.

DETAILED DESCRIPTION OF THE INVENTION

The disclosure herein relates generally to disrupting tissue and devicesand systems for disrupting tissue. More specifically, the disclosuredescribes ways to deliver moieties to a target tissue, where the targettissue in general is not at the point of introduction, in such a waythat minimal damage is produced in the tissue at the point ofintroduction. In some embodiments this is accomplished by jetting fluidat high velocity into the target tissue. The disclosure furtherdescribes novel agents deliverable in such systems for use in remodelingtissues. Some of these agents comprise a liquid while others do not.Additionally, although not specifically described in detail much of thedisclosure may additionally be used in the delivery of therapeuticdrugs.

Procedures that allow for the disruption or remodeling of tissuesperipheral to body lumens, particularly while minimizing disruption tothe inner surface of the body lumen and often the tissues comprising thewall of the body lumen are advantageous in a number of medicalprocedures. Such procedures include but are not limited to: disruptionof nerves in the medial and adventitial tissue surrounding body lumenssuch as arteries and veins, including the renal arteries and pulmonaryarteries and veins, disruption of cancerous tissues surrounding bodylumens such as the esophagus for the treatment of various cancers, andurethra for treatment of various cancers such as prostate cancer. Suchremodeling treatments may additionally be used to shrink tissues such assphincters of the bowel, urethra, stomach, or intestines, amongstothers. Further advantage is obtained when such procedures can beachieved percutaneously, which include endovascular, or minimallyinvasive delivery of the apparatus required to facilitate the procedure.Additionally, the ability to refine or continue the remodeling of thetarget tissue after the completion of the percutaneous or minimallyinvasive procedure has advantages where the outcome of the initialprocedure is unclear for some period of time following the procedure orwhere some level of healing obviates the damage and further remodelingis required. The various configurations of the apparatus and associatedmethods described below facilitate such procedures.

Although the devices described herein are particularly useful fordelivering agents to tissues peripheral to body lumens from within thebody lumen, they also will have application in the delivery of agentsvia pathways and/or in locations independent of body lumens. Such usesinclude treatment of tumor such as those of the liver or lung.

The embodiments described herein associated with the delivery ofmoieties comprising fluids provide one or more of the followingadvantages over that which has been described: improved ways forcontrolling the consistency in dose and or velocity for multi jetsystems across the jets; ways for controlling the dose; use of aconstant pressure source while achieving metered bolus delivery whilemaintaining high initial fluid velocity and control of fluid velocity;and minimizing leakage of delivered material while not in deliverycycle. Additionally, in some embodiments the delivery of the fluid jetsis controlled in a distal region of the delivery system, therebyminimizing negative effects of system capacitance and long fluidchannels on rate at which peak fluid velocity is attained at an exitaperture and delivered dosage. Additionally, damage that is caused bymoving a fluid jet while it is constantly activated and slicing largeareas of tissue may be minimized by minimizing the duration of oncycles.

In some embodiments mechanical disruption of the tissue is effected byhigh velocity fluid jets situated at or near the target site. The jetsmay be located at the inner surface of a body lumen and directed thruthe body lumen towards the target tissue. The jets, as they enter thebody lumen, are highly focused and therefore interact with a small areaof the adjoining lumen wall and volume of adjoining tissue. As the jetpasses through the lumen wall, the fluid interacts with the tissue andis spread over a larger volume of tissue, disrupting an increasinglylarger area of tissue. However, as the area of interaction is increasedthe fluid's direct interaction is dissipated and so is the associateddamage. The direct interaction of the fluid may be to cut, separate, orswell. In some embodiments the jet may be moved to create a slice inadjoining tissue. The jets may additionally be designed such that theshape of the injected fluid volume would be caused to spread in one ortwo directions normal to the forward direction as it enters the tissue.

Alternatively, in some embodiments, the source of the high velocity jetsmay be passed through the inner surface of the lumen wall and into thewall of the body lumen, or the source of the high velocity jets may bepassed completely through the body lumen into the tissue surrounding thebody wall. The apparatus may also be configured such that combinationsof these approaches may be performed.

In some embodiments the fluid delivered via the high velocity injectionsystem is an ablative media such as one of those described below. Anablative material may be delivered to the target tissue without passingany portion of the delivery structure through the wall of the bodylumen. Since needles or other structures capable of fraying or tearingthe body lumen are not passing through the body lumen, no motionsassociated with the delivery of the delivery structure or thoseassociated with movement of the patient can cause damage to the bodylumen. This may be especially important where the body lumen is frail orwhere a tear in the body lumen could cause uncontrollable bleeding.Additionally, the cross section of a jet will be smaller than a deliveryneedle of comparable lumen size.

Some moieties or agents that can necrose tissue, capable of delivery inthe fashion described, are hypertonic or hypotonic solutions whichinduce drying or bursting of cells. In the case of hypertonic, simplesalt solutions and alcohols may be used to these ends. ETOH and mixturesof ETOH and H₂O₂ are particularly useful as such ablative fluids. TheH₂O₂ in this mixture brings about additional damage as a result ofoxidative stress.

Another set of agents useful for necrosing tissues are those whichgenerate heat and can be delivered in the fashion so far described.These materials, upon interaction with each other or the environment ofthe target tissue, generate heat as a result of an ensuing chemicalreaction or solubilization. Examples of materials which when contactedwith water in the target tissue begin a reaction which is exothermicinclude: iron particles, exothermic salts. An exemplary, but incomplete,lists of salts which can be used to this purpose are CaCl₂, CaSO₄,MgSO₄, K₂CO₃, Na₂SO₄. These salts when delivered as a suspension in anon-aqueous carrier, such as a light oil or alcohol amongst others,generate heat upon rehydration. When appropriate masses of salt aredelivered to a small volume of tissue the heat generated from thehydration of the salt and the consumption of water in the localenvironment will both necrose the tissues adjacent to the delivery zone.The conformation of the salts as delivered for this purpose can furtheradd to the heat generating capability. For example, the salts can befinely divided such that surface to volume ratio is increased andtherefore the rate of rehydration and heat generation is enhanced.Finely divided salt particles can range in size from about 0.1 to about100 microns. Especially useful for this purpose would be the suspensionsof nanoparticle sized particles of the salts in which the surface tovolume ratio is even further enhanced. These nanoparticles having a sizerange of 10 nm to 100 nm. Nanoparticles of NaCl, delivered in a lightoil or reagent grade alcohol, upon delivery to a target tissue will uponsolubilization create both an endothermic reaction and a hypertoniclocal environment. The oxidation of iron particles provides anothersystem which will behave in a fashion similar to that just described forthe exothermic salts. Any such system which relies on such reactions andincorporates a particle as part of the delivered material will behave inmuch the same fashion as the salts and iron particles described aboveand will also benefit from an increase in surface to volume ratio suchas that associated with decreasing the size from micron to nanodimensions. Other examples of materials which may be mixed at the targetlocation include acids and bases such as: HCl and NaOH, or weak acidsand metals such as HCl and Mg, catalyzed polymerization reactions suchas that for methyl methacrylate resins, many others can be chosen form,which are familiar to those skilled in the art. An acid or base may alsobe delivered independently of the other. The use of acetic acid is suchan example which has a demonstrated usefulness in ablating tumors.

Yet another set of agents useful for tissue remodeling, where the targettissue are specifically nerve tissues, are nerve toxins such as thebotulinun neurotoxins or capsacin. Many other irreversibly acting nervetoxins, known to those familiar with the art, may be delivered in thisfashion.

In other circumstances blood or blood products may used as an agent. Inthis circumstance the blood may be separated and only plasma used, oralternatively the platelets and cellular material may be used. Whenpreparations containing cells are used the preparation may behomogenized to break down the cell structures. The preparation may alsobe thinned with sodium citrate and or heparin or other anti clottingagents may be added. In yet other circumstances enzymes includingneurolytic and necrotizing may be used. Detergents may also be usedindependently or in combination with any of the fluids described herein.

In some instances it may be advantages for the agent to be deliverablein a low viscosity form and then on interaction with the environment onthe target tissue increases in viscosity possibly becoming a gel. Anacid solution comprising collagen, on introduction to the roughly normalpH of a target tissue, will polymerize forming a resorbable gel likematerial which may additionally comprise nanoparticles or othermaterials described herein.

In some embodiments disruption or remodeling is achieved by anexternally induced interaction between a material delivered to thetarget tissue and the target tissue. Such materials are configured to bedelivered to the target site by percutaneous or minimally invasiveprocedures. Upon completion of material delivery, the material isinduced to facilitate the remodeling by an energy field which is createdat a site external to the body and directed to the target site bynon-invasive means. The induced interactions may be creation or releaseof toxins or necrosing agents, the generation of heat, mechanicaldisruption or any other means which eventuates the necroses or loss infunctionality of cells in the target tissue. These materials mayadditionally contain agents to enhance their contrast when viewed byradiographic, acoustic, or MRI means. It should be noted that thesematerials may also be energized from energy sources delivered minimallyinvasively or percutaneous to locations near the target tissue.

One set of materials which may be used for the generation of heat areinduced to heat by the application of acoustic energy. Examples of suchmaterials include ethyl vinyl acetate, silicone, urethanes and othermaterials known in the art.

Yet another set of materials that can be induced to generate heat arethose capable of absorbing electromagnetic energy, in particularchanging magnetic fields (inductive heating). Examples of such materialsinclude ferrites and other iron bearing materials and materialscontaining Nickel. As an example, heating occurs when an alternating,uniformly high flux density magnetic field induces an alternatingcurrent in a lossy conductor. A gapped toroid can generate such amagnetic field. A solenoid's magnetic field can produce the requiredmagnetic field for inductive heating of discrete particles. In additionto heating particles that have been distributed in the lumen of thebody, the external magnetic field could also be used to couple energyinto a catheter in place of electrical conductors. The external magneticfield could also be used to actuate or position features of the catheterin place of mechanisms (e.g., pull wires etc.).

Yet another use for a magnetic field would be the physical manipulationof a magnetic dipole (or multitude thereof). One use of such amanipulation would be to move a magnetic particle to a desired locationin order to deliver a payload. Another use of such a manipulation wouldbe to move a magnetic particle in such a fashion to be disruptive to thesurrounding tissue. A means for inducing said magnetic manipulationcould be through the use of a 3-dimensional (3D) array of solenoidswhose magnetic fields intersect and form a magnetic field vector thatmanipulates a magnetic particle(s).

In another class of materials the necrosing agent is designed to bereleased or to convert as a function of energy absorption.

The fluid delivery means described herein may be used for the deliveryof therapeutic agents in addition to ablative agents. One suchtherapeutic agent is Taxol, which may be used to minimize post treatmentstenosis. Hypertensive drugs may also be delivered in this fashion.

Any of these materials can be configured for delivery by the mechanismsdescribed above or by more conventional means commonly practiced today,such as the use of simple injection from a needle or system of needlesdelivered to the body lumen in the vicinity of the target tissue. Insuch systems the final spacial geometry of the delivered material may beimportant. Such a situation exists for example with regard to thedenervation or necrosing of adventitial and medial tissue surroundingthe renal artery for the treatment of hypertension. In this situation itcan be advantages to deliver the material in a spiral pattern about thevessel in the adventitial tissue surrounding the vessel.

In some methods of use, an agent can be delivered to renal nerve tissueto disrupt the neural tissue to treat hypertension. The treatment ofhypertension can be accomplished by modulating of neural signaltransmission along the renal nerve. Modulation includes activation ofneural activity, suppression of neural activity, denervation of tissue,ablation of tissue, etc. The relationship between renal nerve signaltransmission and hypertension may be found in, for example, U.S. Pat.No. 6,978,174, U.S. Pat. No. 7,162,303, U.S. Pat. No. 7,617,005, U.S.Pat. No. 7,620,451, U.S. Pat. No. 7,653,438, U.S. Pat. No. 7,756,583,U.S. Pat. No. 7,853,333, and U.S. Pub. No. 2006/0041277, U.S. Pub. No.2006/0206150, U.S. Pub. No. 2006/0212076, U.S. Pub. No. 2006/0212078,U.S. Pub. No. 2006/0265014, U.S. Pub. No. 2006/0265015, U.S. Pub. No.U.S. Pub. No. 2006/0271111, U.S. Pub. No. 2006/0276852, U.S. Pub. No.2007/0129760, and U.S. Pub. No. 2007/0135875, the complete disclosuresof which are incorporated herein by reference. The systems and methodsof use herein can be used to disrupt the tissue to modulate neuraltransmission along a renal nerve in order to treat hypertension.

The above materials may be delivered as solutions with a wide range ofviscosities or be viscous gels. The materials either ablative orotherwise so far described may contain contrast agents and oranesthetics. Additionally, materials may be designed such that oninteracting with the target site the viscosity increases or the materialgels, or mixed on delivery such that they the viscosity increases or thematerial gels at the target site. Alternatively the materials can beformed as a solid designed to be projected into the target tissue thruthe body lumen wall and into the target tissue. Such a mechanism couldbe driven by high velocity fluids, gases, or by mechanical means such assprings.

Any of the above materials can be combined such that they possess any ofthe following characteristics to fit the particular application:bioresorbable, biocompatible, or designed to remain in place forextended periods of time.

Agents which may be added to enhance contrast for imaging procedureswill be dependent on the particular imaging procedure. Examples of suchmaterials which enhance MRI imaging are Gadolinium, magnetic materialsespecially those containing nickel, and or ferrites. Examples of thosefor use with acoustical procedures are silicones, metal or metal oxideparticles, amongst others known in the art. Examples of such materialsuseful for radiological procedures are barium sulfate, tantalum powder,or the like. These examples are not exhaustive and many alternatives,familiar to those skilled in the art may be chosen.

FIG. 1 illustrates an exemplary delivery system adapted to disrupttissue peripheral to a body lumen. Delivery system 10 includes handle 11and elongate delivery member 13. Associated with a distal portion ofelongate member 13 is distal delivery region 14. Distal delivery region14 includes one or more fluid controls 16. Handle 11 includes at leastone delivery member actuation element 12 (two shown), and at least onefluid control actuation element 15 (two shown). Delivery memberactuation element 12 can be adapted to steer delivery member 13,including distal delivery region 14, to a target location within thebody. Delivery member actuation element 12 can also be adapted toreconfigure distal delivery region 14 between a delivery configurationand one or more procedural configurations. Fluid control actuationelement 15 is adapted to actuate fluid controls 16 to effect peripheraltissue remodeling.

FIG. 2 illustrates an exemplary delivery system with a fluid system.Although system 20 is represented as an assembly of components separatefrom handle 11, fluid system 20 may be incorporated within handle 11.Fluid system 20 includes fluid reservoir 21 and optional additionalreservoirs 22. Reservoir(s) interface with pressure source 23 whichprovides the motive force for delivering an agent to fluid controls 16(see FIG. 1). Tissue disruption is mediated by the delivery of an agentfrom the fluid reservoirs to fluid controls 16. Fluid control actuationelement 15 may alternatively be located within fluid system 20.

FIGS. 3-6 illustrate an exemplary embodiment of a delivery systemincorporating a fluid system. Although the exemplary fluid system showncan be incorporated with any of the elongate delivery members herein, asshown in FIG. 3 the fluid system is incorporated into handle 11.Pressure source 23 includes a gas cartridge, such as a CO₂ cartridge,which is in fluid communication with fluid reservoir 21, which in turnis in fluid communication with valve 38, which functions as the fluidcontrol actuation element. In FIG. 3 delivery member actuation element39 facilitates the reconfiguration of distal delivery region 14 from thedelivery configuration shown in FIG. 4 to a procedural, or treatment,configuration shown in FIG. 5. Distal delivery region 14 comprises aplurality of expandable tubular elements 31 that are adapted to bereconfigured from respective delivery configuration as shown in FIG. 4to expanded configurations shown in FIG. 5. In the deliveryconfigurations the tubular elements are generally straight, and insubstantial alignment with the longitudinal axis of the delivery member13. Distal delivery region 14 is shown comprising four tubular elements31 but any suitable number may be incorporated. Tubular elements 31 maybe sealed at their distal ends, and are secured to a distal portion ofouter sheath 36. Tubular elements 31 include ports 35 in fluidcommunication with a fluid source. In the embodiments shown, the portsare formed by removing a portion of the tube wall proximal to the distalends of tubular elements 31. The system includes control member 33 (seeFIG. 5), which is disposed within a portion of sheath 36 proximal todistal delivery region 14. Control member 33 is axially moveable withrespect to the proximal portion of sheath 36 and is fixed to the sheathand tubular elements 31 distal to the distal delivery region. Whencontrol member 33 is actuated in the proximal direction, such as byactuation of delivery member actuation element 39, the distal andproximal ends of tubular elements 31 are urged closer together, causingtubular elements 31 to bend at bending regions 34 radially outward fromthe control member. When bent, the ports 35 are brought into contact, orat least pointed towards the lumen wall in which the distal deliveryregion is positioned. Fluid or agent can then be delivered from thefluid source through ports 35 to disrupt the tissue, which is describedin more detail above. After the treatment has been administered, controlmember 33 is advanced distally with respect to the proximal portion ofsheath 36 to move the ends of the tubular elements away from oneanother, reconfiguring the tubular elements back towards their deliveryconfigurations. When the tubular elements are in their expandedconfigurations, ejection ports 35 are disposed in a plane substantiallynormal to that of the longitudinal axis of elongate delivery member 13.More or fewer elongate tubes can be in the distal delivery regions.Alternatively to the configuration depicted in FIGS. 3-6, the ports 35can be staggered, which may be appropriate for different tissuedisruption treatments. Flexible tubes 31 may be fabricated from anysuitable flexible materials, such as nitinol. In this embodiment controlmember 33 has a lumen and thereby also provides the function of a guidewire lumen.

FIGS. 7-10 illustrate an exemplary method of remodeling of renal nerveplexus 43 surrounding renal artery 40 of kidney 44 using the exemplarysystem shown in FIGS. 3-6. Although the renal nerve plexus is depictedas two nerves for ease of representation, the renal nerve plexusactually wraps around the renal artery. Elongate delivery member 13 withdistal delivery region 14 is delivered from a femoral artery or othersuitable location, using known techniques, to descending aorta 41, theninto renal artery 40. The delivery is facilitated by guidewire 17 whichhas been previously delivered by traditional means to the renal artery.Alternatively, for embodiments which incorporate steering capabilitiesthe delivery may be facilitated without the use of a guide wire. Or inyet other alternative embodiments the delivery may be facilitated by theuse of a steerable introducer catheter such as those described in U.S.patent application Ser. No. 12/823,049, filed Jun. 24, 2009, now U.S.Pat. No. 8,323,241, the disclosure of which is incorporated herein byreference. Upon delivery the distal delivery region 14 is expanded to adelivered configuration as shown in FIG. 8 by actuating the deliverymember actuation element. In some embodiments the actuation element isadvanced distally. The pressure source control element (see element 38in FIG. 3) is activated thereby initiating the delivery of a doseconfigured as a high velocity jet of fluid 51 as indicated in FIG. 9.Single or multiple jets may be delivered while the distal deliver regionis in any given location. The distal delivery region may be moved to anew location by releasing (or further actuating) tissue expansioncontrol element 12 (see FIG. 3), which reconfigures the distal deliveryregion. The distal delivery region can then be moved to a secondlocation, followed by actuation of the tissue interface expansioncontrol element 12. The volume of tissue affected by the delivered fluidcan be controlled by the volume of each individual fluid jet, the numberof jets delivered at any given location, and the number and density oflocations at which jets are delivered. After a desired number of jetsare delivered to an appropriate number of locations, the action of thedelivered fluid will affect a large enough volume of tissue to affect atleast a portion of the renal nerve plexus, herein described as renalnerves, passing through the affected volumes of tissue and indicated inFIG. 10. Any of the systems described herein can be used in the methodshown in the exemplary method of FIGS. 7-10.

FIGS. 11-19 illustrate various distal delivery regions 14. FIG. 11represents a reconfigurable distal delivery region which is an extensionof elongate delivery member 13. In FIG. 11 the distal delivery regioncomprises an elongate tubular element in a treatment, or expanded,configuration. In the delivery configuration (not shown), the elongatetubular element is in a substantially straight configuration. Duringdelivery the distal delivery region 14 substantially co-aligns withelongate delivery member 13 and upon exiting a delivery catheter assumesthe configuration in FIG. 11 because of the resilient characteristics ofthe material. For example, the distal delivery region can be comprisedof nitinol and utilize the superelastic property of nitinol toself-expand when deployed from a delivery catheter. The elongate tubularelement has a generally circular or elliptical configuration such thatthe contact region between the tubular element and the lumen wall fallsroughly in a plane and has an elliptical or circular shape. Someembodiments use devices and methods shown in co-owned U.S. patentapplication Ser. No. 12/823,049, filed Jun. 24, 2009, now U.S. Pat. No.8,323,241, wherein a tensioning element and a compression element areoperated in opposition to one another. The compression elementincorporates a laser cut pattern which collapses into the indicatedshape. In such a configuration the resultant shape and delivery systemcan maintain a great degree of stiffness both along the delivery axis,in torsion, and in maintaining the shape of the tubular element. In FIG.11, distal delivery region 14 also includes fluid control 16, whichincludes at least one fluid jet aperture, discussed in more detailbelow. When distal delivery region 14 transfers from its deliveryconfiguration to its procedural configuration, fluid control 16 is urgedagainst the lumen wall of the target tissue. Distal delivery region 14may be moved from position to position by allowing it to return to itsdelivery configuration or in some cases by moving it in its proceduralconfiguration.

The tissue interface of FIG. 11, although shown with the looped tissueinterface sitting in a plane normal to the delivery axis, mayalternatively be configured such that it is in a plane upon which thedelivery axis exists. Such a configuration may be comprised of asinusoidal tissue interface incorporating one or more cycles of thesinusoid. Additionally each cycle or half cycle may fall on a differentplane rotated from the previous one around the delivery axis.

FIG. 12 illustrates a distal delivery region including an elongatetubular element that has a spiral procedural configuration (as shown),such that the contact regions between the tissue and the tubular elementhave a spiral configuration. The device in FIG. 12 is adapted to beactuated in similar manner to the device in 11. FIG. 13 illustrates adistal delivery region 14 including first and second tubular elements,which are adapted to be actuated in similar fashion to the device inFIG. 12. The elongate tubular elements in FIG. 13 have spiralconfiguration when expanded, and their contact regions with the targetlumen are spiral. The elongate tubular elements shown in FIGS. 12 and 13include a plurality of fluid controls 16. The expanded spiral structuresof FIGS. 12 and 13 urge the associated remodeling elements 16 intocontact with the target lumen. With a plurality of elongate elements asin FIG. 13, forces from the plurality of tubular elements against thelumen wall may create more stable contact regions between the tubularelements and the lumen wall.

FIG. 14 illustrates an exemplary portion of a distal delivery region.Distal delivery region 14 is a variation of that of FIG. 12, wherein thespiral element comprises two spring elements 18 arranged on either sideof shuttle valve 50 incorporating a plurality of fluid controls 16.

FIGS. 15 and 16 illustrate perspective and end views, respectively, ofan alternative embodiment of the distal delivery region. Distal deliveryregion 14 includes a tubular element with a general spiral treatmentconfiguration, and includes a plurality of penetrating remodelingelements 19. Remodeling elements 19 can be used to remodel tissue in anumber of different ways. Procedurally, the distal delivery region isdelivered to a target lumen with penetrating remodeling elements 19retracted with the distal delivery region in a delivery configuration.The elongate element is then reconfigured into a spiral configuration.Remodeling elements 19, which were retracted during delivery, are thenadvanced distally through the elongate element into the configuration asshown in FIGS. 15 and 16. The remodeling elements may then be used toremodel the target tissue by any of mechanical damage resulting fromhigh velocity jet interactions such as cutting or swelling and/orphysical interaction of a cutting or macerating element, delivering atissue disruption agent therethrough, delivering RF energy, or anycombination thereof. Penetrating remodeling elements 19 may comprisefluid controls as described below.

FIGS. 17 and 18 illustrate two variations on the distal delivery regionshown in FIGS. 3-6. In both designs, the distal delivery region controlelement 37 (which has a guide wire lumen therethrough) is retractedproximally relative to outer sheath 36, which foreshortens the distaldelivery region 14. This in turn causes tubular elements 31 to expandand engage the lumen wall. In FIG. 17, each flexible tube incorporatesneedle valves including apertures 52, as described herein. When tubularelements 31 are expanded, fluid apertures 52 are moved into contact withthe lumen wall. In FIG. 17 a section of the outer sheath 36 has beenremoved to show valve control wires 64 extending through the fluidsupply lines 65. The device of FIG. 18 expands in the same fashion, butcomprises shuttle valves (described in more detail herein) rather thanneedle valves.

The exemplary alternative distal delivery region shown in FIG. 18 isshown incorporating four shuttle valves, each comprised of valve movablemember 57 (see FIGS. 21 and 23), a valve stationary member 58 (see FIGS.21 and 23), and a plurality of apertures 60. An alternate way to expanda distal delivery region is to incorporate a balloon. FIGS. 19 and 20show two exemplary distal delivery regions incorporating shuttle valves.Both embodiments comprise a balloon which is contoured to allow bloodflow when the balloon is inflated. Blood flow is maintained in a spiralfluid path adjacent to the lumen contact zone comprising the shuttlevalve. In FIG. 19 fluid control 60 is a shuttle valve incorporatedwithin the balloon 24 and in FIG. 20 fluid control 60 is a shuttle valveincorporated on the balloon. These embodiments may alternativelycomprise traditional non perfusion balloons.

In some situations the delivery devices described herein may beconfigured such that a single fluid control actuates a plurality ofapertures 60.

FIGS. 21-24 illustrate two variations on shuttle valves capable of beingincorporated in a distal delivery region. The valve of FIGS. 21 and 22(FIG. 22 is a close-up view of a portion of the device in FIG. 21)incorporates one or more apertures 52 on outer member 56 of the valve,and an inner member 55, axially moveable with respect to outer member56, incorporating a masking aperture 53. Apertures 52 are smaller thanmasking aperture 53. An individual aperture 52 is selectively addressedwhen the sliding inner masking aperture 53 is slid into a positionadjacent aperture 52. In one configuration, members 55 and 56 are sealedat their distal ends 57 and 58 respectively. Alternatively, the memberadapted to be moved with respect to the other member may be left openwhen the design is such that the length of tubing distal to maskingaperture 53 is long enough to cover all of apertures 52 distal to theaddressed aperture. Inner member 55 and outer member 56 are configuredsuch that the outer diameter of the inner member and the inner diameterof the outer member are closely matched thereby creating an annularregion of minimum cross section and high fluid resistance.Alternatively, or in addition to, the inner movable member or sectionsthereof may be designed such that under the loads experienced whilepressurized it expands and thereby decreases the annular cross sectionthereby further increasing the fluid resistance.

In FIG. 21, by moving larger aperture 53 with respect to smallerapertures 52 such that aperture 53 is in alignment with a given smalleraperture, that smaller apertures 52 can be selectively addressable,increasing the amount of fluid that flows from that valve. When a givenvalve is addressed, the other valves are not addressed. In thisembodiment the valves may be selectively addressable in series. That is,as aperture 53 is moved from a first aperture 52 to a second aperture52, the first and second apertures are selectively addressed in series.Alternatively, when movable member 53 is allowed a rotational degree offreedom around the axis defined by its central lumen, the movable member53 may be rotated 90 degrees and moved past smaller apertures 52 withoutaddressing them, then rotated 90 degrees in the reverse direction whenaligned with the aperture intended to be addressed.

FIGS. 23 and 24 depict an alternative variation on a shuttle valvewherein masking aperture 53 is located on outer stationary member 56 andaperture 52 is located on inner movable member 55. Masking aperture 53can be used to an additional advantage as a mask that creates a field ofview 54 addressable by inner aperture 52. The aperture 52 may be rotatedabout the cylindrical axis of the outer stationary member 56 within themask forming a field of view 54. The field of view 54 forms the core ofthe remodeled volume of damaged tissue peripheral to the lumen. Thefield of view 54 may alternatively describe a slice in the tissueresulting from the jet interaction with the tissue. By rotating aperture52 out of the field of view of masking apertures not intended to beaddressed, any selection of fields of view 54 defined by masks 53 may beaddressed for fluid delivery.

In some embodiments, the fields of views illustrated in FIGS. 23 and 24,and in other embodiments herein, illustrate exemplary patterns in whichtissue is cut or severed by the tissue remodeling therapies describedherein.

The apertures 52 described herein can fall within a range of diameters,or surface areas when not circular in cross section. For delivery flowsin the range of about 1 to about 20 mL/min, diameters of about 0.005 into about 0.0005 in will be of particular value. The aperture should besized such that the peak velocity of the outflow reaches a minimum ofabout 10 m/sec, with about 75 to about 150 m/sec being more optimal forgreater penetration and minimizing erosion. In some situationsvelocities of greater than about 150 m/sec will be useful in achievingeven greater penetration.

The tissue interface means described herein provide for a means ofstabilizing the fluid apertures in contact with tissue in a manner thatminimizes movement of the aperture relative to the adjacent tissue. Therisk of dissections associated with the use of fluid jets is therebyminimized. Additionally, by incorporating of distal fluid controls, theperiod over which agents are delivered can be controlled. By providingjets of agent in short bursts of 1 second or less, preferably 100 msecor less, unexpected movements will result in multiple punctate wounds asopposed to a linear dissection.

Given the relatively small cross sectional areas associated with thefluid apertures in the devices described herein, it is generallyadvisable to filter liquid agents prior to use and/or to incorporatefilters proximal to the distal fluid controls.

FIG. 25 illustrates the spiraled distal delivery region from FIG. 12incorporated with a shuttle valve design from FIG. 23, and expanded inrenal artery 40. The pattern of tissue damage is indicated by fields ofview 54. FIG. 26 illustrates a view normal to the direction of bloodflow demonstrating how the projection of such patterns normal to theaxis of the lumen can produce both dense and overlapping coveragefurther from the lumen and spaced non-overlapping coverage closer to thelumen. The density of jetting structures and associated fields of viewmay be increased to a point where the remodeled zones themselvesoverlap. The associated density and field of view required will bedependent on the particular way in which the damage is created. Given anaperture of relatively small dimension, as illustrated in the smallerapertures described herein, the ratio of the volume of damaged tissueclose to the aperture, seeded by the field of view 54, can be minimizedrelative to volume of damage further away. As illustrated, where thelumen is that of a renal artery, this means minimizing damage toendothelium, tunica intima 46, the tunica media, and tunica adventitia47, with extensive damage to adventitia 48. When desired, the aperture'sfield of view 54 may be increased to correspondingly increase the damageat the tunica media 47. As indicated above any of the fields of viewindicated may be addressed in any sequence by appropriately controllingthe movable member of shuttle valve 23. In this way more or less of therenal nerve may be disrupted.

The devices of FIGS. 21 and 23 may be configured such that only a singlefluid control may be addressed at one time or such that multiple fluidcontrols may be addressed at one time.

FIGS. 27-32 illustrate various configurations and aspects of exemplaryneedle valves that can be activated from the proximal end of thedelivery system, allow for minimal leakage in a closed configuration orhigh fluid resistance when not activated, allow minimal fluid resistancein an open configuration, provide the ability to provide a metered dosefrom the valve, and are capable of both serial or parallel activation.All valves are activated by a valve control member 64, which is adaptedto be axially moved (forward and back) within fluid supply section 65,both of which terminate in a handle (not shown). In some instances thereis also a metering or delivery section 66. In FIGS. 27-29, the needlevalve is supplied by a pressurized fluid source maintained at relativelyconstant pressure which is in fluid communication with the aperture 52via supply section 65, within which is valve control element 64. In anycross section within which valve control member 64 is contained withinthe fluid supply section, there is a relatively non-restrictive fluidflow cross section, shown in FIG. 27 as annular region 63. Distal to thefluid supply section is delivery valve section 66, which in theembodiment of FIGS. 27-29 is of smaller diameter than the supplysection. In association with the valve section is needle element 61which is disposed within delivery section 66. The clearance between theneedle and delivery section lumen is small, such that it forms a narrowrestrictive annular region of relatively high fluid resistance 62 ascompared to that of the lumen with the needle removed. Additionally, thefluid flow cross section of supply section 62 is much smaller than 63.For instance, for a particular concentration of ETOH and water, arestrictive fluid flow cross section created by a 0.5 inch long 0.004inch inner diameter needle in a 0.005 inch inner diameter tube will havea fluid resistance of 450 psi/mL/min. The corresponding resistance forthe same tube without the needle will be approximately 5 psi/mL/min. Incomparison, a supply section created by a 32 inch long tube with a 0.015inch outer diameter and a 0.010 inch outer diameter control wire willhave a corresponding fluid resistance of approximately 1 psi/mL/min. Inthis example the fluid resistance of the system in the openconfiguration is approximately 75 times less than that of the closedsystem, and in a constant pressure environment would leak at a rate ofabout 1/75 the open rate in the closed configuration. In theconfigurations represented in FIGS. 27 and 28, an aperture 52 is createdon the side of delivery section 66 near the sealed distal end. In theconfiguration represented in FIG. 29, the aperture is the open distalend of the delivery section.

A variation on the example of FIGS. 27-29 is represented in FIGS. 30-32.FIG. 30 shows a needle valve in an open configuration where the end ofthe needle is maintained just within the lumen of the delivery section66. In FIG. 31, the valve is partially closed with a section of arestrictive fluid flow cross section 62 indicated. FIG. 32 shows thevalve fully closed with the distal face of the guide 69 seated againstthe proximal face of the end seal of the supply section 65. If required,further increases in fluid resistance can be attained in the fullyclosed position by incorporating an elastomeric guide 69 or anelastomeric distal face to guide 69 which would seal against theproximal face of the end seal on the supply section 65. Guide 69additionally incorporates relieved areas to create a large fluid flowcross section 63.

FIGS. 33-35 illustrate an exemplary embodiment of a metering valveconfiguration. Guide 69 is configured such that it forms a narrowrestrictive annular aperture with the end of the delivery section 66,which in this configuration may be the end of the supply section 65.When the valve control member 64 is actuated proximally, fluid leaksacross the restrictive fluid flow cross section 62, filling the distalmetered volume 67. At this point the fluid resistance between the supplyside and the delivery side is the sum of that associated with the exitaperture 52 and the restrictive cross section 62. When the valve controlmember 64 is released the resistance associated with fluid flow acrosscross section 62 goes to zero and the guide moves as a plug of deliveryfluid. The movement of the guide imparts minimal additional fluidresistance to the system, thereby allowing the pressure across aperture52 to attain levels comparable to those seen with no guide in place.This state remains in effect until the guide runs into the distal sealedend 68 of the delivery section 66, as shown in FIG. 35. At this pointthe outflow resistance becomes that associated with the restrictivefluid flow cross section 62 and aperture 52 again. In this way, thedelivered volume—that volume delivered under high pressure and at highvelocity which penetrates the intima—is that which was disposed distalto the guide plug prior to its release. The delivered volume cantherefore be regulated and controlled, and can be adjustable. Ifrequired, the rate at which the guide is withdrawn during the fill cyclecan be matched to that of the expected fluid flow across restrictivefluid flow cross section 62 such that there is minimal negative pressuregenerated across the guide 69. This configuration behaves differentlythan other control elements in that the fluid resistance across thecontrol element remains constant but the position of the control elementis allowed to change. As illustrated the travel of the guide 69 isdefined by the amount of proximal displacement of the guide from thedistal end seal 68 which acts as its stop. In an alternate embodiment,not shown, the displacement of the guide 69 may be controlled byalternate mechanisms and the guides displacement may terminate proximalto the end seal 68.

FIGS. 36 and 37 illustrate the distal delivery region of FIGS. 15 and 16deployed within a section of renal artery 40. In FIG. 36 the end ofelongate delivery member 13 just distal to distal delivery region 14 canbe seen centered in the vessel. Penetrating remodeling elements 19 havebeen deployed from their non-deployed configuration within the distaldelivery region to their deployed state, penetrating through intimal 46and medial layer 47 of the vessel and terminating in the adventitiallayer 48. Volumes of remodeled tissue 45 spiral through the adventitia,with one intersecting nerve 43. FIG. 37 depicts a view normal to theaxis of blood flow for the vessel in which can be seen that the primaryvolume of remodeled tissue occurs beyond the intimal and adventitiallayers.

In yet another embodiment as depicted in FIG. 38, a penetratingremodeling element 19 is a needle. The needle has a helicalconfiguration and delivered while contained with an outer sheath of adelivery section 13 of a delivery system, not shown. In thisconfiguration, the outer sheath of the delivery section has a stiffnesssufficient to maintain the spring element in a straightenedconfiguration. On delivery the remodeling element is pushed distally outof the distal end of the outer sheath of the delivery system until thedistal end of the remodeling element has passed into the vessel wall.The remodeling element is then twisted, which in combination with thepre-set spiral configuration allows the remodeling element 16 to screwits way around the vessel within the adventitial layer. The remodelingelement can be comprised of a number of different configurations. Inmany of these configurations it is a conductor that may be powered withRF to deliver energy sufficient to ablate the surrounding tissue.Alternatively, it may be powered in such a way as to electroporate thesurrounding tissue. The remodeling element may additionally be poroussuch that an ablating agent (described herein) may be delivered throughthe porous structure. It may alternatively be coated with an ablativeagent. In those embodiments where it is used to deliver an ablativeagent on or through its walls and it is conductive the electroporativecapability may be used to enhance the action of the ablative compounddelivered. When the remodeling element is comprised of a needle, it mayalso be used to leave an ablative element in the tract of its path asthe element is removed by a procedure in reverse of that by which it wasdelivered. The material left may alternatively be one designed to absorbenergy provided by an external source such as a gel containing a ferriteas mentioned elsewhere in this application.

In any of the configurations relying on the delivery of a fluid agent athigh velocity, the pressure may be adjusted between delivery cycles. Inthis manner the volume and spatial characteristics of the remodeledtissue volume may be adjusted. Of particular value in such a situationis the incorporation of a contrast agent within the delivered mediawhich will provide visual feedback on the remodeled volume via theparticular imaging means. Such imaging means include but are not limitedto CT, MRI, and ultrasound.

FIG. 42 provides a figurative representation of a delivery systemincorporating a distal fluid control configured as a shuttle valve,while a representation of its fluidic performance is illustrated in FIG.39. The system comprises a fluid and pressure source 20, which feeds adelivery system 10, as generally described above. The delivery system iscomprised of elongate delivery member 13 comprising a fluid supplysection feeding into distal delivery region 14, which comprises a fluidcontrol terminating in aperture 52 from which a jet of fluid 51 isejected under appropriate conditions of alignment. FIG. 40 is afigurative representation of the delivery system in terms of itsresistive fluidic characteristics. The elements are the fluid resistanceof the fluid source 83 contained within elongate delivery member 13, thefluid resistance of the fluid path within the tissue interface portion84, and the fluid resistance of control port 80. Each of these elementshas an associated capacitance which is not shown in this representation.The control port behaves as a variable resistance which is the primarycharacteristic under control. FIGS. 40 and 41 illustrate various aspectsof the resistive fluidic performance of these components. FIG. 40represents the resistance associated with the fluid control port 80, asa function of the displacement “d” of its control element position, andthe resistances for the supply section and tissue interface portions ofthe system 83 and 84 respectively, which are not directly controllablein this configuration and are essentially fixed. Key positions for thejet aperture 52 relative to the masking aperture 53 are indicated on thedisplacement axis d as “0”, “a”, and “b”. The point “0” corresponds tothe position where the proximal edge of the jet exit aperture alignswith the proximal edge of the jet masking aperture. The position “a”corresponds to the point at which the distal edge of the jet aperturealigns with the distal edge of the masking aperture, and b represents apoint where the proximal edge of the jet exit aperture is distal to thedistal edge of the jet masking aperture by some distance a-b. As seen inthe illustration, the fluid resistance versus displacementcharacteristics of the shuttle valve fluid control 80 has two distinctperformance features. A constant resistance 82 is demonstrated initiallywhich is equal to that associated with the cross section of the jet exitaperture. A second increasing resistance 81 is demonstrated when the jetaperture passes out of the masking aperture. This resistance increasesas the distance d increases. FIG. 41 illustrates a representation of theexpected outflow rate 90 as a function d given the resistancecharacteristics represented in FIG. 40 and a constant pressure supply.Outflow rate 90 is comprised of a high constant rate of outflow 91 fordisplacements “0” to “a” and a decreasing rate of outflow 92 fordisplacements “a” to “b”. The regions represented by displacements “0”to “a” correspond to the on state and the displacement “b” correspond tothe off state. The system resistance will be the sum of the componentresistances. The scales indicated should be understood as arbitrary andthe magnitude of the difference in flow and resistance in the off stateversus the on state may be a few times to multiple orders of magnitude.

FIG. 43 shows the system of FIG. 39 wherein the shuttle valve isreplaced by a needle valve. This system demonstrates fluidic behaviorsimilarly to that described for the shuttle valve variation. Howevercertain differences associated with actuation and fabrication arenotable and delineated below. In a system incorporating multipleindividually and selectively addressable fluid controls, the shuttlevalve based system may be configured such that control elements arecomprised of two parts as is illustrated in FIGS. 21-24 above. Theneedle valve and metered valve variations by contrast require a separatecontrol element and associated controllable member for each valveseparately addressable. In the needle valve variation the variableresistance associated with the control element 80 is shifted to theposition of the tissue interface 84, the resistance of the tissueinterface and the jet exit apertures in the most distal position. Suchan arrangement does not lend itself to a serial arrangement as themultiple valves require a common source which is proximal to the controlelement.

Given the small size of many of the critical features associated withthe above described fluid controls and the extreme sensitivity of theperformance of the fluid controls to the dimensions of these features,the ability to serially and or individually address each fluid controlhas particular value where uniformity of delivery is required. Forinstance, an individual device may be calibrated in such a fashion thatthe outflow resistance for each outflow is known and used to adjust theeither or both the static source pressure or the on time such that eachoutflow behaves similarly with reference to the fluid delivery during aninjection cycle. In addition, as noted above, the fluid media deliveredmay contain a contrast agent and the operator can use the visualinformation to change the source pressure to vary depth of penetration,duration of injection to adjust volume delivered, or provide multipleinjection cycles at a given location to adjust volume of targetedtissue. The delivery cycle may additionally be spread out over time suchthat an initial volume is injected at an initial time, then anadditional volume is injected at a later time where enough time isallowed such that information on the rate of diffusion of the deliveredfluid is gained and additional volumes may then be delivered in afashion wherein the a concentration of ablatant sufficient to ablate ismaintained in the remodeled target volume for a sufficient time toremodel the tissue.

FIG. 44 represents yet another alternative for effecting tissueremodeling where a fluid, gas, or mechanical rod may be used to eject acomponent capable of external excitation as described herein oralternatively a component which upon ejection springs into a shapedifferent than its delivery shape and in so doing damages tissue in itsvicinity, thereby causing tissue remodeling. In FIG. 44 spring elements101 are shown after ejection from distal delivery region 30 through thewall of renal artery 40. As shown, multiple spring elements 101 havebeen ejected from two separate positions of distal delivery region 30.Spring elements 101 may be configured such that the tines are heldtogether for a period of time past the ejection cycle. For instance theymay be held together by a water soluble binder and injected in a gas,oil, or alcohol carrier. In this fashion, on residing within the tissuefor a period of time the binder will be solubalized and the tinesreleased. The release of the tines may be used to cut or macerate thetissue surrounding the tines.

It has been demonstrated in the literature that the volume of tissueaffected by a needleless injection will be dependent on the spatialvelocity and temporal velocity profiles of the injectate at the time ofdelivery. In particular, delivering a volume of fluid into a tissue massat high initial velocity minimizes tissue damage at the entry pointwhile allowing fluid to penetrate deep into the tissue. Maintaining theoutflow at a lower velocity after the initial penetration facilitates anincrease in volume delivered through the initial wound. In the abovedescribed fluid delivery systems, the control mechanism has beenincorporated at the distal region of the delivery system. This allowsthe delivery system to be maintained at delivery pressures and therebyminimizes the filtering effects of the long narrow delivery lumens andsystem capacitance on the velocity profile of ejected fluid at the exitaperture.

In another alternative embodiment of a tissue remodeling device cuttingor macerating devices may be delivered through or in the manner thatneedles 16 in FIGS. 36 and 37 are delivered. Such devices may beconfigured as slicing hooks or simple blades which cut on being pushedas represented in FIG. 45. Additionally such devices may be spun as anatherectomy blade to facilitate the requisite remodeling as depicted inFIG. 46 through which the rotatable cutting device of FIG. 45 isdelivered. FIG. 47 shows a device as in FIG. 36. While preferredembodiments of the present disclosure have been shown and describedherein, it will be obvious to those skilled in the art that suchembodiments are provided by way of example only. Numerous variations,changes, and substitutions will now occur to those skilled in the artwithout departing from the disclosure. It should be understood thatvarious alternatives to the embodiments of the disclosure describedherein may be employed in practicing the disclosure.

1.-7. (canceled)
 8. A method for treating a human patient with diagnosedhypertension, the method comprising: positioning an elongate deliverymember having a distal fluid delivery region within a renal blood vesseland proximate to renal nerves of the patient; transforming the fluiddelivery region from a low-profile delivery configuration to an expandedtreatment configuration, wherein the fluid delivery region comprises aplurality of tubular elements, and wherein, in the expanded treatmentconfiguration, each tubular element is bent along a bending region ofthe respective tubular element to position a portion of the individualtubular elements in contact with a wall of the renal blood vessel;delivering a neuromodulatory fluid via one or more of the tubularelements to attenuate or block neural signaling along the renal nerves;and removing the elongate delivery member and fluid delivery region fromthe patient after delivering the neuromodulatory fluid to conclude theprocedure.
 9. The method of claim 8 wherein positioning the elongatedelivery member having the distal fluid delivery region within a renalblood vessel comprises intravascularly delivering the elongate deliverymember and fluid delivery region through an abdominal aorta to a renalartery of the patient.
 10. The method of claim 8 wherein positioning theelongate delivery member having the distal fluid delivery region withina renal blood vessel comprises delivering the elongate delivery memberto the renal blood vessel via a guidewire.
 11. The method of claim 8wherein the fluid delivery region of the elongate delivery membercomprises a control member axially movable with respect to the elongatedelivery member, and wherein distal and proximal end regions of thetubular elements are fixed to the control member, and further wherein:transforming the fluid delivery region from a low-profile deliveryconfiguration to an expanded treatment configuration comprises actuatingthe control member in a proximal direction to urge the distal andproximal end regions of the individual tubular elements toward eachother, thereby causing the tubular elements to bend along thecorresponding bending regions outward away from the control member andtoward the wall of the renal blood vessel.
 12. The method of claim 11,further comprising actuating the control member in a distal directionafter delivering the neuromodulatory fluid to urge the distal andproximal end regions of the individual tubular elements away from eachother, thereby transforming the fluid delivery region from the expandedtreatment configuration back to the low-profile delivery configurationbefore removing the elongate delivery member and fluid delivery regionfrom the patient.
 13. The method of claim 8 wherein the tubular elementseach include one or more ports for delivery of the neuromodulatory fluidtherethrough, and wherein each tubular element is in fluid communicationwith a fluid source configured to store the neuromodulatory fluid. 14.The method of claim 13 wherein, when the fluid delivery region is in theexpanded treatment configuration, each port is in contact with or facingthe wall of the renal blood vessel.
 15. The method of claim 13 wherein:when the fluid delivery region is in the treatment configuration, eachof the ports faces in a direction different from the direction it facesin when the fluid delivery region is in the delivery configuration. 16.The method of claim 13 wherein delivering a neuromodulatory fluid viaone or more of the tubular elements to attenuate or block neuralsignaling along the renal nerves comprises delivering theneuromodulatory fluid simultaneously through the ports.
 17. The methodof claim 8 wherein delivering the neuromodulatory fluid to attenuate orblock neural signaling along the renal nerves results in atherapeutically beneficial reduction in one or more symptoms associatedwith the hypertension of the patient.
 18. The method of claim 8 whereindelivering a neuromodulatory fluid to attenuate or block neuralsignaling along the renal nerves comprises delivering theneuromodulatory fluid to at least partially ablate the renal nerves. 19.The method of claim 8 wherein delivering a neuromodulatory fluid toattenuate or block neural signaling along the renal nerves comprisesdelivering the neuromodulatory fluid to tissue external to the renalblood vessel of the patient and in contact with or adjacent to the renalnerves.
 20. The method of claim 8 wherein delivering a neuromodulatoryfluid to attenuate or block neural signaling along the renal nervescomprises delivering alcohol.
 21. The method of claim 8 whereindelivering a neuromodulatory fluid to attenuate or block neuralsignaling along the renal nerves comprises delivering a neurotoxin. 22.The method of claim 8 wherein delivering a neuromodulatory fluid toattenuate or block neural signaling along the renal nerves comprisesdelivering botulinum toxin.
 23. The method of claim 8 wherein the renalblood vessel is a first renal artery and the renal nerves are firstrenal nerves, and wherein the method further comprises: after deliveringthe neuromodulatory fluid to attenuate or block neural signaling alongthe first renal nerves, introducing the elongate delivery member to asecond renal artery of the patent and proximate to second renal nerves;delivering the neuromodulatory fluid via one or more of the tubularelements to attenuate or block neural signaling along the second renalnerves; and after delivering the neuromodulatory fluid to the secondrenal nerves, removing the elongate delivery member and fluid deliveryregion from the patient to conclude the procedure.
 24. The method ofclaim 8 wherein, when the fluid delivery region is in the expandedtreatment configuration, it does not occlude the renal blood vessel. 25.An apparatus for controllably releasing fluid within a hypertensivehuman patient, the apparatus comprising: an elongate shaft having adistal portion configured for intravascular placement within a renalartery of the patient; and a fluid delivery assembly including aplurality of tubular elements at the distal portion of the catheter,wherein the fluid delivery assembly is selectively transformable betweena low-profile, delivery configuration and a deployed configuration sizedto fit within the renal artery of the patient, wherein, when the fluiddelivery assembly is in the delivery configuration, the tubular elementsare generally straight and in alignment with a longitudinal axis of theelongate shaft, wherein, when the fluid delivery assembly is in thedeployed configuration, the assembly is arranged in a basket-like shapeadapted to allow blood to flow therethrough and the tubular elements areeach bent outwardly away from the longitudinal axis such that a portionof each tubular element is in apposition with a wall of the renalartery; and wherein each tubular element comprises a fluid deliveryaperture and is configured when the fluid delivery assembly is in thedeployed configuration to deliver a fluid agent via the respectiveaperture to target renal nerves of the patient in an amount sufficientto modulate neural function of the targeted renal nerves.
 26. Theapparatus of claim 25 wherein the tubular elements are composed ofnitinol.
 27. The apparatus of claim 25 wherein the distal portion of theelongate shaft is configured for intravascular placement within therenal artery over a guidewire.
 28. The apparatus of claim 25 whereineach of the plurality of fluid delivery apertures is adapted to beselectively addressable to regulate a volume of the fluid agentdelivered via the respective fluid delivery apertures.